Radenkovic Silvia, Adant Isabelle, Bird Matthew J, Swinnen Johannes V, Cassiman David, Kozicz Tamas, Gruenert Sarah C, Ghesquière Bart, Morava Eva
Laboratory of Applied Mass Spectrometry, Department of Molecular and Cellular Medicine, KU Leuven, 3000 Leuven, Belgium.
Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, 3000 Leuven, Belgium.
Cells. 2025 Apr 25;14(9):638. doi: 10.3390/cells14090638.
Inherited metabolic disorders (IMDs) are genetic disorders that occur in as many as 1:2500 births worldwide. Nevertheless, they are quite rare individually and even more rare is the co-occurrence of two IMDs in one individual. To better understand the metabolic cross-talk between glycosylation changes and deficient energy metabolism, and its potential effect on outcomes, we evaluated patient fibroblasts with likely pathogenic variants in and pathogenic variants in derived from a patient who passed away at 16 years of age. The patient presented with characteristic of PGM1-CDG including bifid uvula, muscle involvement, abnormal glycosylation in blood, and elevated liver transaminases. In addition, hearing loss, seizures, elevated plasma and CSF lactate and a Leigh-like MRI brain pattern were present, which are commonly associated with Leigh syndrome. PGM1-CDG has been reported in about 70 individuals, while deficiency has so far only been reported in 13 patients. As abundant energy is essential for glycosylation, and both and are linked to energy metabolism, we sought to better understand the underlying biochemical cause of the patient's clinical presentation. To do so, we performed extensive investigations including tracer metabolomics, lipidomics and enzymatic studies on the patient's fibroblasts. We found a profound depletion of UDP-hexoses, consistent with PGM1-CDG. Complex I enzyme activity and mitochondrial function were also impaired, corroborating complex I deficiency and Leigh syndrome. Further, lipidomics analysis showed similarities with both PGM1-CDG and OXPHOS-deficient patients. Based on our results, the patient was diagnosed with both PGM1-CDG and Leigh syndrome. In summary, we present the first case of combined CDG and Leigh syndrome, caused by (likely) pathogenic variants in and , and underline the importance of considering the synergistic effects of multiple disease-causing variants in patients with complex clinical presentation, leading to the patient's early demise.
遗传性代谢紊乱（IMDs）是一种遗传性疾病，在全球范围内每2500例出生中就有1例发生。然而，它们个体发病率相当低，而一个人同时患有两种IMDs的情况更为罕见。为了更好地理解糖基化变化与能量代谢缺陷之间的代谢相互作用及其对疾病结局的潜在影响，我们评估了一名16岁去世患者的成纤维细胞，该细胞存在可能的致病变体和致病变体。该患者表现出PGM1 - CDG的特征，包括悬雍垂裂、肌肉受累、血液中糖基化异常以及肝转氨酶升高。此外，还存在听力丧失、癫痫发作、血浆和脑脊液乳酸升高以及类似Leigh综合征的脑部MRI表现，这些通常与Leigh综合征相关。据报道，PGM1 - CDG患者约有70例，而缺陷迄今为止仅在13例患者中报道过。由于充足的能量对于糖基化至关重要，且和都与能量代谢相关，我们试图更好地理解该患者临床表现的潜在生化原因。为此，我们对患者的成纤维细胞进行了广泛的研究，包括示踪代谢组学、脂质组学和酶学研究。我们发现UDP - 己糖严重耗竭，这与PGM1 - CDG一致。复合物I酶活性和线粒体功能也受损，证实了复合物I缺乏和Leigh综合征。此外，脂质组学分析显示该患者与PGM1 - CDG患者和氧化磷酸化缺陷患者均有相似之处。基于我们的结果，该患者被诊断为同时患有PGM1 - CDG和Leigh综合征。总之，我们报告了首例由和（可能）致病变体导致的联合性先天性糖基化障碍（CDG）和Leigh综合征病例，并强调在具有复杂临床表现的患者中考虑多种致病变体协同效应的重要性，这些变体导致了患者的过早死亡。
